1,2-Dihydro-6-phenyl-1H,4H-imidazobenzodiazepin-1-ones

ABSTRACT

Novel 1,2-dihydro-6-phenyl-1H,4H-imidazo[1,2-a][1,4]-benzodiazepin-1-ones of the formula ##STR1## wherein R is selected from the group consisting of hydrogen, halogen, nitro and trifluoromethyl, R 1  is selected from the group consisting of hydrogen and halogen, R 2  is selected from the group consisting of hydrogen and methyl and R 3  and R 4  are individually selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms, hydroxyalkyl of 1 to 5 carbon atoms, aminoalkyl of 1 to 5 carbon atoms, mono-and di-alkylaminoalkyl with each alkyl having 1 to 5 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and mono and di-nuclear aryl or R 3  and R 4  taken together with the nitrogen atom to which they are attached form a saturated heterocycle which may contain a second heteroatom optionally substituted with at least one member of the group consisting of alkyl of 1 to 5 carbon atoms, hydroxyalkyl of 1 to 5 carbon atoms, dialkylphosphinylalkyl with 1 to 5 carbon atoms in the alkyl groups, cycloalkylalkyl with 3 to 6 carbon atoms in the ring and 1 to 5 alkyl carbon atoms, alkenyl of 2 to 5 carbon atoms, phenyl and nitrogen heterocycles and their non-toxic, pharmaceutically acceptable acid addition salts having sedative, hypnotic, anxiolytic, tranquilizing, anticonvulsive and myorelaxant properties and their preparation.

PRIOR APPLICATION

This application is a division of our copending, commonly assigned U.S. patent application Ser. No. 791,845 filed Apr. 28, 1978, now U.S. Pat. No. 4,134,976 which in turn is a division of copending, commonly assigned U.S. Pat. application Ser. No. 658,301 filed Feb. 17, 1976, now U.S. Pat. No. 4,044,142.

STATE OF THE ART

French Pat. No. 2,183,716 describes benzodiazepines but they are differently substituted than the compounds of formula I and have tranquilizing properties.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel compounds of formula I and their non-toxic, pharmaceutically acceptable acid addition salts and their preparation.

It is another object of the invention to provide novel therapeutic compositions and a novel method of treating agitated states, insomnia and psychosomatic syndromes in warm-blooded animals.

These and other objects and advantages of the invention will become obvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are 1,2-dihydro-6-phenyl-1H,4H-imidazo-[1,2-a] [1,4]-benzodiazepin-1-ones of the formula ##STR2## wherein R is selected from the group consisting of hydrogen, halogen, nitro and trifluoromethyl, R₁ is selected from the group consisting of hydrogen and halogen, R₂ is selected from the group consisting of hydrogen and methyl and R₃ and R₄ are individually selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms, hydroxyalkyl of 1 to 5 carbon atoms, aminoalkyl of 1 to 5 carbon atoms, mono- and di- alkylaminoalkyl with each alkyl having 1 to 5 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and mono and di-nuclear aryl or R₃ and R₄ taken together with the nitrogen atom to which they are attached form a saturated heterocycle which may contain a second heteroatom optionally substituted with at least one member of the group consisting of alkyl of 1 to 5 carbon atoms, hydroxyalkyl of 1 to 5 carbon atoms, dialkylphosphinylalkyl with 1 to 5 carbon atoms in the alkyl groups cycloalkylalkyl with 3 to 6 carbon atoms in the ring and 1 to 5 alkyl carbon atoms, alkenyl of 2 to 5 carbon atoms, phenyl and nitrogen heterocycles and their non-toxic, pharmaceutically acceptable acid addition salts.

When R and R₁ are halogen, they may be fluorine, chlorine or bromine and R is preferably chlorine and R₁ is preferably fluorine or chlorine in the ortho position although it may be in other positions. R₂ is preferably hydrogen.

R₃ and R₄ may be alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl or pentyl but is preferably a linear alkyl of 1 to 4 carbon atoms. Examples of hydroxyalkyl are hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or hydroxypentyl but is preferably hydroxyethyl. Examples of aminoalkyl and mono- and dialkylaminoalkyl groups are those where the alkyl may be methyl, ethyl, propyl, butyl but preferably are methyl or ethyl. Specific groups are preferably aminomethyl, aminoethyl, dimethylaminoethyl and diethylaminoethyl but may also be aminopropyl, aminobutyl, methylaminomethyl, methylaminoethyl and dimethylaminopropyl. When R₃ or R₄ are aryl, they may be phenyl or naphthyl, preferably phenyl. An example of cycloalkyl of 3 to 8 carbon atoms is cyclohexyl. When R₃ and R₄ are different, one of them is preferably hydrogen.

When R₃ and R₄, together with the nitrogen atom to which they are attached form a heterocyclic, it is saturated and may be substituted or unsubstituted and may optionally contain a second heteroatom. Examples of unsubstituted heterocyclics are pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazin-1-yl. Preferred substituents for such heterocyclic groupings are alkyls of 1 to 5 carbon atoms such as methyl, ethyl and propyl; hydroxyalkyls of 1 to 5 carbon atoms such as hydroxyethyl; dialkylphosphinylalkyls, each alkyl moiety of which contains from 1 to 5 carbon atoms such as methyl; cycloalkylalkyls with 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 alkyl carbon atoms such as cyclopropylmethyl; alkenyls of 2 to 5 carbon atoms such as allyl; phenyl; and nitrogen heterocyclic radicals such as 1-phenyl-5-imidazolyl-4-one.

Typical examples of substituted heterocyclics are the 4-alkyl-piperazin-1-yls and especially 4-methyl-, 4-ethyl and 4-propyl-piperazin-1-yl; the 4-hydroxyalkyl-piperazin-1-yls and especially 4-hydroxyethyl-piperazin-1-yl; the 4-dialkylphosphinylalkyl-piperazin-1-yls and especially 4-dimethylphosphinylmethyl-piperazin-1-yl; the 4-cycloalkylalkyl-piperazin-1-yls and especially 4-cyclopropylmethyl-piperazin-1-yl; 4-alkenyl-piperazin-1-yls and especially 4-allyl-piperazin-1-yl; 4-phenyl-piperazin-1-yl; and 4-(1'-phenyl-5'-imidazoyl-4'-one)-piperidin-1-yl.

A preferred group of compounds are the imidazolobenzodiazepines of formula I wherein R₃ and R₄ are individually selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms, hydroxyethyl, dimethyl- or diethylaminoethyl, phenyl and cyclohexyl or R₃ and R₄ together with the nitrogen atom form a member of the group consisting of pyrrolidinyl, piperidino, morpholino, thiomorpholino, piperazin-1-yl, 4-alkyl-piperazin-1-yl, 4-hydroxyalkyl-piperazin-1-yl, 4-phenyl-piperazin-1-yl and 4-(1'-phenyl-5'-imidazolyl-4'-one) piperidin-1-yl.

A second preferred group of compounds are the imidazolobenzodiazepines of formula I wherein R is chlorine or nitro, R₁ is selected from the group consisting of hydrogen, chlorine and fluorine, R₂ is hydrogen, and R₃ and R₄ are individually selected from the group consisting of hydrogen, straight alkyl of 1 to 5 carbon atoms, hydroxyethyl, phenyl and cyclohexyl, or R₃ and R₄ together with the nitrogen atom form a member selected from the group consisting of piperidino, morpholino, piperazin-1-yl, 4-alkyl-piperazin-1-yl and 4-hydroxyethyl-piperazin-1-yl.

A third preferred group of compounds are the imidazolobenzodiazepines of formula I wherein R is chlorine or nitro, R₁ is hydrogen, chlorine or fluorine, R₂ is hydrogen, and R₃ is hydrogen and R₄ is methyl, ethyl, propyl and butyl, or R₃ and R₄ together with the nitrogen atom form a member selected from the group consisting of piperazin-1-yl, 4-methyl piperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-propyl-piperazin-1-yl and 4-hydroxyethyl-piperazin-1-yl.

A fourth group of preferred compounds are the imidazolobenzodiazepines of formula I wherein R is chlorine or nitro, R₁ is hydrogen, chlorine or fluorine, R₂ is hydrogen, and R₃ and R₄ together with the nitrogen atom form a 4-methylpiperazin-1-yl, 4-ethyl-piperazin-1-yl or 4-propyl-piperazin-1-yl radical.

A fifth group of preferred compounds are the imidazolobenzodiazepines of formula I wherein R is hydrogen, chlorine or nitro, R₁ is hydrogen, chlorine or fluorine, R₂ is hydrogen and R₃ and R₄ together with the nitrogen atom form a 4-dialkylphosphinylalkyl-piperazin-1-yl radical; and the imidazolobenzodiazepines of formula I wherein R is hydrogen, chlorine or nitro, R₁ is hydrogen or chlorine, R₂ is hydrogen and R₃ and R₄ together with the nitrogen atom form a 4-dimethylphosphinylmethyl-piperazin-1-yl radical.

The imidazolobenzodiazepines I may be in the form of non-toxic, pharmaceutically acceptable acid addition salts which may be salts with mineral or organic acids. Typical mineral acids are hydrochloric acids, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid, while typical organic acids are acetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkanesulfonic acids and arylsulfonic acids. Preferred acid addition salts are the tartrates and alkanesulfonates, and the methanesulfonates are especially preferred.

Further preferred groups of compounds of the invention in the form of acid addition salts are the acid addition salts of imidazolobenzodiazepines of formula I wherein R is hydrogen, chlorine or nitro, R₁ is hydrogen, chlorine or fluorine, R₂ is hydrogen and R₃ and R₄ together with the nitrogen atom form a 4-alkyl-piperazin-1-yl radical; and the tartrates and alkanesulfonates (particularly methanesulfonates) of the imidazolobenzodiazepines of formula I wherein R is chlorine or nitro, R₁ is hydrogen or chlorine, R₂ is hydrogen and R₃ and R₄ together with the nitrogen atom form a 4-methylpiperazin-1-yl or a 4-ethyl-piperazin-1-yl.

Specific preferred imidazolobenzodiazepines of formula I and their non-toxic, pharmaceutically acceptable salts are:

8-chloro-1,2-dihydro-2-(N-methyl-piperazin-1-yl)methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

8-chloro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one tartrate;

8-chloro-1,2-dihydro-2(N-hydroxyethyl-piperazin-1-yl methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

8-chloro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

8-chloro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one tartrate;

8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

8-chloro-1,2-dihydro-2-(n-butyl-amino) methylene-6-phenyl-1H,4H-imidazo[1,2-a][1,4]-benzodiazepin-1-one;

8-chloro-1,2-dihydro-2-(n-methyl-piperazin-1-yl) methylene-6-(o-fluorophenyl)-1H,4H-imidazol-[1,2-a][1,4]-benzodiazepin-1-one;

8-chloro-1,2-dihydro-2-(n-propylamino) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one methanesulfonate;

8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-(o-fluorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

8-chloro-1,2-dihydro-2-(N-ethyl-piperazin-1-yl)methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

8-chloro-1,2-dihydro-2-(N-propyl-piperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

8-chloro-1,2-dihydro-2-(N-ethyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

8-chloro-1,2-dihydro-2-(N-ethyl-piperazin-1-yl)methylene-6(o-fluorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

8-nitro-1,2-dihydro-2-(N-ethyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

8-nitro-1,2-dihydro-2-(N-ethyl-piperazin-1-yl) methylene-6-(o-fluorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

3-chloro-1,2-dihydro-2-(ethylamino) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one:

8-chloro-1,2-dihydro-2-(N-dimethylphosphinylmethylpiperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

8-chloro-1,2-dihydro-2-(N-dimethylphosphinylmethylpiperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one;

1,2-dihydro-2-(N-dimethylphosphinylmethyl-piperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one; and

8-nitro-1,2-dihydro-2-(N-dimethylphosphinylmethylpiperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one. Of these specific preferred compounds, 8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one methanesulfonate has shown a particularly remarkable pharmacological activity.

The imidazolobenzodiazepines of formula I may be prepared by reacting a compound of the formula ##STR3## wherein R and R₁ have the above definition and glycine and alkyl esters thereof, preferably in an organic solvent such as an alcohol like ethanol at elevated temperatures such as the reflux temperature to obtain a compound of the formula ##STR4## wherein R' is hydrogen or alkyl and reacting the latter with a dehydrating agent such as carbodiimide like dicyclohexylcarbodiimide in a chlorinated alkane such as methylene chloride or subjecting the latter to pyrolysis in a high boiling solvent such as toluene to obtain the corresponding 8-R-1,2-dihydro-6-(R₁ -phenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one of the formula ##STR5## wherein R and R₁ have the above definition.

To obtain a compound of formula I wherein R₂ is hydrogen and R₃ and R₄ are methyl, the compound of formula IV may then be reacted with a dimethylformamide acetal of the formula ##STR6## wherein AlK is alkyl of 1 to 5 carbon atoms, preferably in an anhydrous organic solvent such as benzene in the presence of a base such as triethylamine or other nitrogen base or amine to form a compound of the formula ##STR7## wherein R and R₁ have the above definition.

To produce the compounds of formula I wherein R₂, R₃ and R₄ are all methyl, the compound of formula IV is reacted with N,N-dimethylacetamide preferably in an anhydrous organic solvent such as a chlorinated alkane like methylene chloride at a temperature below room temperature, i.e. below 10° C. in the presence of a condensation promoter such as phosphorus oxychloride to obtain a compound of the formula ##STR8## wherein R and R₁ have the above definition.

To obtain the compounds of formula I wherein R₃ and R₄ are other than methyl, the compounds of formula Ia and Ib are transaminated with the appropriate amine or ammonia, preferably in an anhydrous organic solvent such as toluene at elevated temperatures such as reflux to obtain the corresponding compound of the formula ##STR9## wherein R, R₁ and R₂ have the above definition and R₃ ' and R₄ ' are the same as R₃ and R₄ other than methyl.

The compounds of formula Ic may be further reacted, if necessary, to introduce the substituent on the heterocyclic ring. When ##STR10## wherein R" is cycloalkylalkyl or alkenyl or dialkylphosphinylalkyl, the corresponding piperazinyl-1-yl compound is reacted with R"-Hal to form the corresponding R"-piperazin-1-yl compound.

To produce the compounds of formula Ic wherein ##STR11## are 4-dialkylphosphinylalkyl-piperazin-1-yl, the compound of formula Ic is reacted with piperazine and the resulting compound is reacted with a haloalkyl dialkylphosphineoxide to obtain the corresponding 2-(n-dialkylphosphinylalkyl-piperazin-1-yl) compound. The latter reaction is preferably effected with the chloroalkyl-dialkylphosphine oxide in an organic solvent such as toluene.

The acid addition salts of the compounds of formula I may be formed by reaction with a substantially stoichiometric amount of the desired acid in an organic solvent such as alkanols such as methanol or ethanol or alkyl halides such as methylene chloride.

The 2-carboxymethylamino-7-R-5-(R₁ -phenyl)-3H-1,4-benzodiazepines of formula III and the corresponding 2-alkoxy carbonylmethylamino-7-R-5-(R₁ -phenyl)-3H-1,4-benzodiazepines wherein the alkoxy group is other than ethoxy of formula III are novel products.

The novel pharmaceutical compositions of the invention are comprised of an effective amount of at least one compound of formula I and its non-toxic, pharmaceutically acceptable acid addition salts and a pharmaceutical carrier. The compositions may be in the form of a tablet, coated tablets, sublingual tablet, capsules, cachets, suppositories, syrups, drinkable solutions or suspensions and injectable solutions or suspensions.

The compositions may contain the usual pharmaceutical excipients such as talc, gum arabic, lactose, starch, animal or vegetable fats and oils, magnesium stearate, cacao butter, aqueous or non-aqueous liquids, paraffinic derivatives glycols, wetting agents, dispersing agents, emulsifiers and preservatives.

The pharmaceutical compositions of the invention have sedative, hypnotic, anxiolytic, tranquilizing, anticonvulsive and myorelaxant activities and are useful for the treatment of states of agitation and irritability, states of aggression, insomnia, certain psychosomatic syndromes, certain character and behavior disorders and muscular contractions or spasms.

The novel method of the invention for treating agitated states, insomnia and psychosomatic syndromes in warm-blooded animals, including humans, comprises administering to warm-blooded animals an effective amount of at least one compound of formula I and its non-toxic, pharmaceutically acceptable acid addition salts. The compounds may be administered orally, rectally or transcutaneously and the usual daily dose is 0,02 to 1 mg/kg depending upon the compound and the method of administration.

In the following examples there are described several preferred embodiments to illustrate the invention. However, it is to be understood that the invention is not intended to be limited to the specific embodiments.

EXAMPLE 1 8-chloro-1,2-dihydro-2-(dimethylamino) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one STEP A: 2-carboxymethylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine

A suspension of 3.5 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione, 5.5 g of glycine, 5.5 g of sodium carbonate, 100 ml of ethanol and 30 ml of water was refluxed with stirring for an hour and the mixture was poured into water. The pH of the solution was adjusted to 4 by addition of 2 N hydrochloric acid and was extracted with chloroform. The mixture was filtered and the filtrate was dried over magnesium sulfate and evaporated to dryness. The gummy residue was crystallized by trituration with methanol and the mixture was filtered. The recovered solid was crystallized from ethanol to obtain 3.1 g (77% yield) of 2-carboxymethylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine melting at 215°-220° C.

STEP B: 8-chloro-1,2-dihydro-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one

2.1 g of dicyclohexylcarbodiimide were added with stirring to a suspension of 2.5 g of 2-carboxymethylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine in 120 ml of anhydrous methylene chloride and the mixture was stirred at room temperature for 3 hours and was filtered. The filtrate was evaporated to dryness to obtain 8-chloro-1,2-dihydro-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one in the form of a colorless oil which was used as is for the next step.

STEP C: 8-chloro-1,2-dihydro-2-(dimethylamino) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one

1.5 g of dimethylformamide diethyl acetal and 1 ml of triethylamine were added to a solution of the product of Step B in anhydrous benzene and the mixture was stirred at room temperature for 90 minutes. The mixture was evaporated to dryness and the brown-yellow residue was crystallized from ethyl acetate-methanol to obtain 2.7 g (97% yield) of 8-chloro-1,2-dihydro-2-(dimethylamino) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one in the form of pale yellow rods melting at 264°-265° C.

Analysis: C₂₀ H₁₇ Cl N₄ O; molecular weight=364.9 Calculated: %C 65.85 %H 4.66 %N 15.37 %Cl 9.74 Found: 65.87 4.67 15.37 9.79

I.R. Spectra (KBr disc):

C═0 at 1690 cm⁻¹ ; C═N at 1621 cm⁻¹.

EXAMPLE 2

Using the procedure of Example 1, glycine was reacted with the appropriate benzodiazepine-2-thione to obtain a 66% yield of 2-carboxymethylamino-7-nitro-5-phenyl-3H-1,4-benzodiazepine which after crystallization melted at 154°-155° C. The said product was reacted with dicyclohexylcarbodiimide to form 8-nitro-1,2-dihydro-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one which was used as is for the reaction with dimethylformamide diethyl acetal to obtain after crystallization from methanol a 43% yield of 8-nitro-1,2-dihydro-2-(dimethylamino) methylene-6-phenyl-1H,4H-imidazo [1,2-a][1,4]-benzodiazepin-1-one melting at 227°-228° C.

EXAMPLE 3

Using the procedure of Example 1, glycine was reacted with the appropriate benzodiazepine-2-thione to obtain a 75% yield of 2-carboxymethylamino-7-chloro-5-o-chlorophenyl-3H-1,4-benzodiazepine which after crystallization from methanol-ethyl ether melted at 136°-139° C. The said product was reacted with dicyclohexylcarbodiimide to form 8-chloro-1,2-dihydro-6-o-chlorophenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one which was used as is for the reaction with dimethylformamide diethyl acetal to obtain after crystallization from methanol-ethyl ether a 53% yield of 8-chloro-1,2-dihydro-2-(dimethylamino) methylene-6-o-chlorophenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one melting at 288°-290° C.

EXAMPLE 4

Using the procedure of Example 1, glycine was reacted with the appropriate benzodiazepine-1-thione to obtain a 83% yield of 2-carboxymethylamino-7-nitro-5-o-chlorophenyl-3H-1,4-benzodiazepine which after crystallization from ethyl ether melted at 158°-161° C. The said product was reacted with dicyclohexylcarbodiimide to form 8-nitro-1,2-dihydro-6-o-chlorophenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one which was used as is for the reaction with dimethylformamide diethyl acetal to obtain after crystallization from methanol a 78% yield of 8-nitro-1,2-dihydro-2-(dimethylamino) methylene-6-o-chlorophenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one melting at 253°-255° C.

EXAMPLE 5

Using the procedure of Example 1, glycine was reacted with the appropriate benzodiazepine-2-thione to obtain a 69% yield of 2-carboxymethylamino-7-chloro-5-o-fluorophenyl-3H-1,4-benzodiazepine in the form of a gum. The said product was reacted with dicyclohexylcarbodiimide to form 8-chloro-1,2-dihydro-6-o-fluorophenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one which was used as is for the reaction with dimethylformamide diethyl acetal to obtain after crystallization from methanol a 63% yield of 8-chloro-1,2-dihydro-2-(dimethylamino) methylene-6-o-fluorophenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one melting at 257°-260° C.

EXAMPLE 6

Using the procedure of Example 1, glycine was reacted with the appropriate benzodiazepine-2-thione to obtain a 44% yield of 2-carboxymethylamino-7-nitro-5-o-fluorophenyl-3H-1,4-benzodiazepine which was crystallized from ethyl ether. The said product was reacted with dicyclohexylcarbodiimide to form 8-nitro-1,2-dihydro-6-o-fluorophenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one which was used as is for the reaction with dimethylformamide diethyl acetal to obtain after crystallization from methanol a 80% yield of 8-nitro-1,2-dihydro-2-(dimethylamino) methylene-6-o-fluorophenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one melting at 228°-231° C.

EXAMPLE 7 8-chloro-2-[1'-(dimethylamino)ethylidene]-1,2-dihydro-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one

3.7 g of phosphorus oxychloride were added dropwise over 5 minutes with stirring to a solution of 8-chloro-1,2-dihydro-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one in 200 ml of methylene chloride and 2.0 g of dimethylacetamide cooled to 0° C. and the mixture was stirred for 20 hours at room temperature and was poured into 500 ml of saturated sodium bicarbonate solution. The mixture was stirred until carbon dioxide evolution ceased and the aqueous layer was extracted twice with 100 ml of methylene chloride. The combined organic extracts were washed with saturated sodium bicarbonate solution and then water, were dried over magnesium sulfate and evaporated to dryness to obtain a yellow solid residue. The product was crystallized from a chloroformethyl ether mixture to obtain 2.3 g (40% yield) of 8-chloro-2-[1'-(dimethylamino)ethylidene]-1,2-dihydro-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one melting at 251°-252° C.

Analysis: C₂₁ H₁₉ Cl N₄ O; molecular weight=378.9 Calculated: %C 66.58 %H 5.02 %N 14.79 %Cl 9.38; Found: 66.32 4.91 14.77 9.02

I.R. Spectra (KBr disc):

C═0 at 1653 cm⁻¹ ; C═N at 1610 cm⁻¹

EXAMPLE 8 8-chloro-1,2-dihydro-2-(N-methylpiperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one and its tartrate STEP A:

A mixture of 2.3 g of 8-chloro-1,2-dihydro-2-(dimethylamino) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one and 4.0 g of N-methyl-piperazine in 50 ml of anhydrous toluene was refluxed for 24 hours and was cooled. The mixture was filtered and the filtrate was evaporated to dryness. The pale yellow residue was treated with methanol and the solution was filtered. The solid was crystallized from an ethyl acetate-methanol mixture to obtain 2.3 g (87% yield) of 8-chloro-1,2-dihydro-2-(N-methylpiperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one melting at 255°-256° C.

Analysis: C₂₃ H₂₂ Cl N₅ O; molecular weight=419.9 Calculated: %C 65.80 %H 5.24 %N 16.69 %Cl 8.46 Found: 65.64 5.27 16.63 8.56

I.R. Spectra (KBr disc):

C═0 at 1705 cm⁻¹ ; C═N at 1635 cm⁻¹

STEP B:

A stoichiometic amount of the said product and tartaric acid in methanol was prepared and the mixture was filtered. The product was crystallized from methanol to obtain the tartrate of the said product melting at 146°-150° C.

Analysis: C₂₇ H₂₈ Cl N₅ O₇ ; molecular weight=570.1 Calculated: %C 56.89 %H 4.92 %N 11.29 %Cl 6.23 Found: 56.44 4.93 11.79 5.93

I.R. Spectra (KBr disc):

OH at 3400 cm⁻¹ and 2500 cm⁻¹ ; C═0 at 1730 cm⁻¹ and 1690 cm⁻¹, C═N at 1630 cm⁻¹.

EXAMPLES 9 TO 40

Using the procedure of Example 8, the 1,2-dihydro-2-(dimethylamino) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one was reacted with the appropriate amine compound to obtain the following compounds.

    ______________________________________                                         Example                                                                        ______________________________________                                          9    8-chloro-1,2-dihydro-2-(morpholino) methylene-6-                               phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin                                1-one.                                                                   10    8-chloro-1,2-dihydro-2-(N-hydroxyethyl-piperazin-1-                            yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-                             benzodiazepin-1-one.                                                     11    8-chloro-1,2-dihydro-2-(N-phenyl-piperazin-1-yl)                               methylene-6-phenyl-1H,4H-imidazo-[ 1,2-a][1,4]-benzo-                          diazepin-1-one.                                                          12 and                                                                               8-chloro-1,2-dihydro-2-(N-methyl-piperazin-1-yl)                          12 B methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a]                             [1,4]-benzodiazepin-2-one and its tartrate.                              13    8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl)                                methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzo-                           diazepin-1-one.                                                          14    8-chloro-1,2-dihydro-2-(piperazin-1-yl) methylene-6-                           phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-                               1-one.                                                                   15    8-chloro-1,2-dihydro-2-(n-butyl-amino) methylene-6-                            phenyl-1H,4H-imidazo- [1,2-a][1,4]-benzodiazepin-1-one.                  16    8-chloro-1,2-dihydro-2-(piperidino) methylene-6-                               phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin                                1-one.                                                                   17    8-chloro-1,2-dihydro-2-(thiomorpholino) methylene-6-                           phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-                               1-one.                                                                   18    8-chloro-1,2-dihydro-2-(diethylaminoethylamino)                                methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzo                            diazepin-1-one.                                                          19    8-chloro-1,2-dihydro-2-(N-methyl-N-(dimethylamino)                             ethylamino) methylene-6-phenyl-1H,4H-imidazo-[1,2-a]                           [1,4]-benzodiazepin-1-one.                                               20    8-chloro-1,2-dihydro-2-(methylamino) methylene-6-                              phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-                               1-one.                                                                   21    8-chloro-1,2-dihydro-2-(cyclohexylamino) methylene-                            6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-                             1-one.                                                                   22    8-chloro-1,2-dihydro-2-(N-methyl-piperazin-1-yl)                               methylene-6-(o-fluorophenyl)-1H,4H-imidazo-[1,2-a]                             [1,4]-benzodiazepin-1-one.                                               23    8-chloro-1,2-dihydro-2-[4-(1'-phenyl-5'-imidazolyl-                            4'-one)piperidin-1-yl] methylene-6-phenyl-1H,4H-                               imidazo-[1,2-a][1,4]-benzodiazepin-1-one.                                24    8-chloro-1,2-dihydro-2-(phenylamino) methylene-6-                              phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-                             one.                                                                     25    8-chloro-1,2-dihydro-2-(t-butylamino) methylene-6-                             phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-                               1-one.                                                                   26    8-chloro-1,2-dihydro-2-(hydroxyethylamino) methylene                           6-phenyl-1H,4H-imidazo-[ 1,2-a][1,4]-benzodiazepin-                            1-one.                                                                   27    8-chloro-1,2-dihydro-2-(n-propylamino) methylene-6-                            phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-                               1-one.                                                                   28    8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl)                                methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[ 1,2-a]                            [1,4]-benzodiazepin-1-one.                                               29    8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl)                                methylene-6-(o-fluorophenyl)-1H,4H-imidazo-[ 1,2-a]                            [1,4]-benzodiazepin-1-one.                                               30 and                                                                               8-chloro-1,2-dihydro-2-(N-ethyl-piperazin-1-yl)                           30 B methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzo-                           diazepin-1-one and its tartrate.                                         31    8-chloro-1,2-dihydro-2-(N-propyl-piperazin-1-yl)                               methylene-6-phenyl-1H,4H-imidazo-[ 1,2-a][1,4]-benzo-                          diazepin-1-one.                                                          32    8-chloro-1,2-dihydro-2[N-(n-butyl)-piperazin-1-yl]                             methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzo-                           diazepin-1-one.                                                          33    8-chloro-1,2-dihydro-2-(N-ethyl-piperazin-1-yl)                                methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a]                             [1,4]-benzodiazepin-1-one.                                               34    8-chloro-1,2-dihydro-2-(N-ethyl-piperazin-1-yl)                                methylene-6-(o-fluorophenyl)-1H,4H-imidazo[ 1,2-a]                             [1,4]-benzodiazepin-1-one.                                               35    8-nitro-1,2-dihydro-2-(N-ethyl-piperazin-1-yl)                                 methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a]                             [1,4]-benzodiazepin-1-one.                                               36    8-nitro-1,2-dihydro-2-(N-ethyl-piperazin-1-yl)                                 methylene-6-(o-fluorophenyl)-1H,4H-imidazo[  1,2-a]                            [1,4]-benzodiazepin-1-one.                                               37    8-chloro-1,2-dihydro-2-(ethylamino) methylene-6-                               phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-                               1-one.                                                                   38    8-chloro-1,2-dihydro-2-(N-propyl-piperazin-1-yl)                               methylene-6-o-chlorophenyl-1H,4H-imidazo-[1,2-a]                               [1,4]-benzodiazepin-1-one.                                               39    8-chloro-1,2-dihydro-2-(ethylamino) methylene-6-                               o-chlorophenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodia-                            zepin-1-one.                                                             40    8-chloro-1,2-dihydro-2-(n-propylamino) methylene-6-                            o-chlorophenyl-1H,4H-imidazo-[1,2-a][1,4]-benzo-                               diazepin-1-one.                                                          ______________________________________                                    

EXAMPLE 41 8-chloro-1,2-dihydro-2-(amino) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one

2.1 g of 8-chloro-1,2-dihydro-2-(dimethylamino) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one were suspended in 100 ml of anhydrous methanol and the suspension was stirred and cooled in a dry-ice acetone bath. Ammonia gas was bubbled through the mixture for 15 minutes and the suspension was then warmed to room temperature, stirred for a further two days, and the solvent was evaporated. The solid residue was crystallized from a methanol-ethyl acetate mixture to obtain 1.9 g (98% yield) of 8-chloro-1,2-dihydro-2-(amino) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one melting at 265°-267° C.

EXAMPLE 42 8-chloro-1,2-dihydro-2-[1-(N-methyl-piperazino)-ethylidene]-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one

2.3 g of 8-chloro-2-[1'-(dimethylamino)-ethylidene]1,2-dihydro-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one and 15 ml of N-methyl-piperazine were stirred at 120° C. under a nitrogen atmosphere for 9 hours. The cooled solution was poured into water and sodium chloride was added to complete precipitation. The brown precipitate was filtered off and dissolved in CHCl₃. The solution was washed with water, dried over MgSO₄, and evaporated to dryness to obtain a dark red oil. The oil crystallized on triturating with ether-methanol, and was crystallized from ethyl acetate to obtain 1.0 g (38% yield) of 8-chloro-2[1'-(N-methylpiperazin-1-yl)-ethylidene]-1,2-dihydro-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one melting at 193°-195° C.

EXAMPLE 43 8-chloro-1,2-dihydro-2-[N-(isopropyl)-piperazin-1-yl] methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin- 1-one

1.5 g of 8-chloro-1,2-dihydro-2-(piperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one, 2.5 g of isopropyl iodide and 3.0 g of sodium carbonate were stirred at 80° C. in 25 ml of acetonitrile and 5 ml of methylene chloride for 18 hours. The cooled solution was poured into water and was extracted with chloroform. The extracts were washed with water, dried over MgSO₄, and evaporated to dryness to obtain a pale yellow solid. Crystallization of the solid from ethyl acetate gave 1.2 g (73% yield) of 8-chloro-1,2-dihydro-2-(N-isopropyl-piperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one melting at 146°-148° C.

EXAMPLES 44-45

Using the procedure of Example 43, the following compounds were prepared:

    ______________________________________                                         44  8-chloro-1,2-dihydro-2-(N-allyl-piperazin-1-yl)                                methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzo-                           diazepin-1-one melting at 187°-188° C.                       45  8-chloro-1,2-dihydro-2-(N-cyclopropylmethyl-piper-                             azin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a]                            [1,4]-benzodiazepin-1-one melting at 202°-204° C.            ______________________________________                                    

EXAMPLE 46 8-chloro-1,2-dihydro-2-(N-dimethylphosphinylmethyl-piperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one

A mixture of 2.5 g of 8-chloro-1,2-dihydro-2-(piperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one, 1.5 g of chloromethyldimethylphosphine oxide and 5.0 g of sodium carbonate in 80 ml of toluene was stirred under reflux for 3 days. The cooled suspension was distributed between chloroform and water and the chloroform extract was separated, dried over MgSO₄, and evaporated to dryness to obtain a pale yellow oil which crystallized with methanol. The solid (unrequired by-product) was filtered off and the filtrate was evaporated to give a pale orange oil. This oil was dissolved in chloroform and chromatographed on Kieselgel.

Elution with chloroform-methanol (5%) gave a pale yellow solid, which on crystallization from methylene chloride-ether gave 1.25 g (41% yield) of 8-chloro-1,2-dihydro-2-(N-dimethylphosphinylmethyl-piperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one melting at 261°-262° C.

The analysis of 1R spectra for the compounds of Examples 9 to 46 are reported in the following Table.

    __________________________________________________________________________                                                  Infrared Spectra                                              Analyses         cm.sup.-1 (KBr Disc)              Formula Ib/1c      Molecular                                                                               Found/Calculated              melting              Examples                                                                            R  R.sub.1                                                                          --N(R.sub.3) (R.sub.4)                                                                 Formula   M.Wt.                                                                              %C %H %N %Cl NH , OH                                                                             C═O                                                                            C═N                                                                            point                __________________________________________________________________________                                                               °C.            9   Cl H morpholino                                                                             C.sub.22 H.sub.19 ClN.sub.4 O.sub.2                                                      406.9                                                                              64.89                                                                             4.68                                                                              13.79                                                                             8.87                                                                               --   1695                                                                               1630                                                                               223-4                                                64.95                                                                             4.68                                                                              13.78                                                                             8.73                                  10   Cl H N-hydroxyethyl-                                                                        C.sub.24 H.sub.24 ClN.sub.5 O.sub.2                                                      450.0                                                                              63.91                                                                             5.41                                                                              15.59                                                                             8.15                                                                               3380 1690                                                                               1630                                                                               177-9                          piperazin-1-yl        64.07                                                                             5.34                                                                              15.57                                                                             7.90                                                                               (OH)                              11   Cl H N-phenylpip-                                                                           C.sub.28 H.sub.24 ClN.sub.5 O                                                            482.0                                                                              69.68                                                                             5.10                                                                              14.39                                                                             7.48                                                                               --   1695                                                                               1630                                                                               206-8                          erazin-1-yl           69.77                                                                             4.98                                                                              14.54                                                                             7.37                                  12   Cl Cl                                                                               N-methylpip-                                                                           C.sub.23 H.sub.21 Cl.sub.2 N.sub.5 O                                                     455.4                                                                              60.91                                                                             4.72                                                                              15.35                                                                             15.46                                                                              --   1695                                                                               1625                                                                               247-8                          erazin-1-yl           60.80                                                                             4.66                                                                              15.41                                                                             15.61                                 12B  Cl Cl                                                                               N-methylpip-                                                                           C.sub.27 H.sub.27 Cl.sub.2 N.sub.5 O.sub.7                                               604.5                                                                              -- -- -- --  --   --  --  155-160                        erazin-1-yl           53.66                                                                             4.50                                                                              11.59                                                                             11.73                                 13   NO.sub.2                                                                          H "       C.sub.23 H.sub.22 N.sub.6 O.sub.3                                                        430.5                                                                              63.80                                                                             5.17                                                                              19.54                                                                             --  --   1692                                                                               1635                                                                               284-6                                                64.18                                                                             5.12                                                                              19.54                                                                             --                                    14   Cl H piperazin-1-yl                                                                         C.sub.22 H.sub.20 ClN.sub.5 O                                                            405.9                                                                              65.05                                                                             5.03                                                                              17.25                                                                             9.09                                                                               3300 1695                                                                               1625                                                                               233-5                                                65.10                                                                             4.93                                                                              17.26                                                                             8.75                                                                               (NH)                              15   Cl H N-butylamino                                                                           C.sub.22 H.sub.21 ClN.sub.4 O                                                            392.9                                                                              66.96                                                                             5.46                                                                              14.13                                                                             9.24                                                                               3200 1690                                                                               1638                                                                               165-7                                                67.25                                                                             5.35                                                                              14.27                                                                             9.04                                                                               (NH)                              16   Cl H piperidino                                                                             C.sub.23 H.sub.21 ClN.sub.4 O                                                            404.9                                                                              68.08                                                                             5.29                                                                              14.13                                                                             8.77                                                                               --   1690                                                                               1625                                                                               249-50                                               68.24                                                                             5.23                                                                              13.84                                                                             8.73                                  17   Cl H thiomorpholino                                                                         C.sub.22 H.sub.19 ClN.sub.4 OS                                                           422.9                                                                              62.02                                                                             4.62                                                                              13.05                                                                             --  --   1700                                                                               1630                                                                               255-8                                                62.49                                                                             4.53                                                                              13.25                                                                             8.36                                  18   Cl H diethylamino                                                                           C.sub.24 H.sub.26 ClN.sub.5 O                                                            436.0                                                                              66.38                                                                             6.28                                                                              16.26                                                                             8.04                                                                               3210 1690                                                                               1640                                                                               113-6                          ethylamino            66.13                                                                             5.97                                                                              16.07                                                                             8.15                                                                               (NH) --  1630                     19   Cl H N-methyl-N-                                                                            C.sub.23 H.sub.24 ClN.sub.5 O                                                            422.0                                                                              65.33                                                                             5.71                                                                              16.27                                                                             8.50                                                                               --   1690                                                                               1630                                                                               152-5                          (dimethylamino)-      65.49                                                                             5.37                                                                              16.60                                                                             8.38                                            ethylamino                                                           20   Cl H methylamino                                                                            C.sub.19 H.sub.15 ClN.sub.4 O                                                            350.9                                                                              64.86                                                                             4.46                                                                              15.74                                                                             10.20                                                                              3300 1690                                                                               1620                                                                               233-5                                                65.07                                                                             4.31                                                                              15.98                                                                             10.08                                                                              (NH)                              21   Cl H cyclohexyl-                                                                            C.sub.24 H.sub.23 ClN.sub.4 O                                                            419.0                                                                              68.35                                                                             5.78                                                                              13.53                                                                             8.18                                                                               3420 1695                                                                               1635                                                                               143-5                          amino                 68.82                                                                             5.49                                                                              13.39                                                                             8.48                                                                               (NH)                              22   Cl F N-methylpip-                                                                           C.sub.23 H.sub.21 ClFN.sub.5 O                                                           438.0                                                                              62.44                                                                             4.91                                                                              15.68                                                                             8.57                                                                               --   1700                                                                               1630                                                                               249-51                         erazin-1-yl           63.08                                                                             4.83                                                                              15.59                                                                             8.09                                  23   Cl H 4-(1'-phenyl-                                                                          C.sub.31 H.sub.27 ClN.sub.6 O.sub.2                                                      551.1                                                                              -- -- -- --  3400 1715                                                                               1620                                                                               289-91                         5'-imidazoyl-         67.57                                                                             4.94                                                                              15.25                                                                             6.43                                                                               (NH) 1680                                   4'-one)piper-                                                                  idin-1-yl                                                            24   Cl H phenylamino                                                                            C.sub.24 H.sub.17 ClN.sub.4 O                                                            412.9                                                                              69.61                                                                             4.19                                                                              13.40                                                                             8.97                                                                               3400 1690                                                                               1650                                                                               249-51                                               68.82                                                                             4.15                                                                              13.57                                                                             8.59                                                                               (NH) 1678                         25   Cl H t-butylamino                                                                           C.sub.22 H.sub.21 ClN.sub.4 O                                                            392.9                                                                              -- -- -- --  3320 1690                                                                               1640                                                                               230-2                                                67.26                                                                             5.39                                                                              14.26                                                                             9.02                                                                               (NH)                              26   Cl H hydroxyethyl                                                                           C.sub.20 H.sub.17 ClN.sub.4 O.sub.2                                                      380.9                                                                              62.98                                                                             4.72                                                                              14.65                                                                             9.58                                                                               3280 1700                                                                               1630                                                                               223-5                          amino                 63.08                                                                             4.50                                                                              14.71                                                                             9.31                                                                               (NH)                              27   Cl H n-propylamino                                                                          C.sub.21 H.sub.19 ClN.sub.4 O                                                            378.9                                                                              66.48                                                                             5.09                                                                              14.64                                                                             9.43                                                                               3230 1700                                                                               1630                                                                               153-5                                                66.58                                                                             5.02                                                                              14.79                                                                             9.38                                                                               (NH)                              28   NO.sub.2                                                                          Cl                                                                               N-methylpip-                                                                           C.sub.23 H.sub.21 ClN.sub.6 O.sub.3                                                      465.0                                                                              59.31                                                                             4.68                                                                              18.00                                                                             7.85                                                                               --   1690                                                                               1630                                                                               214-5                          erazin-1-yl           59.43                                                                             4.55                                                                              18.08                                                                             7.63                                  29   NO.sub.2                                                                          F "       C.sub.23 H.sub.21 FN.sub.6 O.sub.3                                                       448.5                                                                              61.43                                                                             4.83                                                                              18.82                                                                             --  --   1690                                                                               1630                                                                               303-6                                                61.60                                                                             4.72                                                                              18.74                                                                             --                                    30   Cl H N-ethylpip-                                                                            C.sub.24 H.sub.24 ClN.sub.5 O                                                            434.0                                                                              -- -- -- --  --   1695                                                                               1630                                                                               183-4                          erazin-1-yl           66.43                                                                             5.57                                                                              16.14                                                                             8.17                                  30 R Cl H N-ethyl-                                                                               C.sub.28 H.sub.30 ClN.sub.5 O.sub.7                                                      584.1                                                                              56.55                                                                             5.16                                                                              11.44                                                                             6.15                                                                               3400 1710                                                                               1630                                                                               143-7                          piperazin-            57.57                                                                             5.13                                                                              11.99                                                                             6.08                                                                               2500 1690                                   1-yl                                                                 31   Cl H N-propylpip-                                                                           C.sub.25 H.sub.26 ClN.sub.5 O                                                            448.0                                                                              -- -- -- --  --   1695                                                                               1630                                                                               148-52                         erazin-1-yl           67.03                                                                             5.85                                                                              15.63                                                                             7.91                                  32   Cl H N-(n-butyl)-                                                                           C.sub.26 H.sub.28 ClN.sub.5 O                                                            462.0                                                                              67.46                                                                             6.16                                                                              15.10                                                                             7.73                                                                               --   1697                                                                               1630                                                                               186-7                          piperazin-1-yl        67.61                                                                             6.07                                                                              15.17                                                                             7.69                                  33   Cl Cl                                                                               N-ethyl-pip-                                                                           C.sub.24 H.sub.23 Cl.sub.2 N.sub.5 O                                                     469.4                                                                              61.75                                                                             5.11                                                                              14.35                                                                             15.03                                                                              --   1695                                                                               1632                                                                               243-5                          erazin-1-yl           61.54                                                                             4.95                                                                              14.95                                                                             15.14                                 34   Cl F N-ethyl-piper-                                                                         C.sub.24 H.sub.23 ClFN.sub.5 O                                                           452.0                                                                              63.04                                                                             5.17                                                                              15.19                                                                             7.96                                                                               --   1697                                                                               1637                                                                               235-7                          azin-1-yl             63.19                                                                             5.13                                                                              15.50                                                                             7.84                                  35   NO.sub.2                                                                          Cl                                                                               N-ethyl-piper-                                                                         C.sub.24 H.sub.23 ClN.sub.6 O.sub.3                                                      480.0                                                                              60.25                                                                             4.90                                                                              17.45                                                                             7.86                                                                               --   1697                                                                               1640                                                                               265-7                          azin-1-yl             60.19                                                                             4.81                                                                              17.56                                                                             7.42                                  36   NO.sub.2                                                                          F N-ethyl-piper-                                                                         C.sub.24 H.sub.23 FN.sub.6 O.sub.3                                                       462.5                                                                              62.28                                                                             5.15                                                                              17.95                                                                             --  --   1693                                                                               1630                                                                               262-4                          azin-1-yl             62.33                                                                             5.01                                                                              18.17                                                                             --                                    37   Cl H Ethylamino                                                                             C.sub.20 H.sub.17 ClN.sub.4 O                                                            364.8                                                                              65.36                                                                             4.72                                                                              15.03                                                                             9.56                                                                               3250 1690                                                                               1640                                                                               234-6                                                65.85                                                                             4.66                                                                              15.37                                                                             9.74                                                                               (NH)                              38   Cl Cl                                                                               N-(N-   C.sub.25 H.sub.25 Cl.sub.2 N.sub.5 O                                                     483.5                                                                              62.31                                                                             5.28                                                                              14.67                                                                             14.67                                                                              --   1696                                                                               1632                                                                               247-9                          propyl)-              62.24                                                                             5.22                                                                              4.52                                                                              14.52                                           piperazin-1-yl                                                       39   Cl Cl                                                                               Ethylamino                                                                             C.sub.20 H.sub.16 Cl.sub.2 N.sub.4 O                                                     399.3                                                                              60.21                                                                             4.05                                                                              13.90                                                                             17.95                                                                              3280 1700                                                                               646 235-1646                                             60.16                                                                             4.04                                                                              14.03                                                                             17.76                                                                              (NH)                              40   Cl Cl                                                                               n-propylamino                                                                          C.sub.21 H.sub.18 Cl.sub.2 N.sub. 4 O                                                    413.4                                                                              61.02                                                                             4.37                                                                              13.36                                                                             17.32                                                                              3240 1695                                                                               1640                                                                               227-9                                                61.03                                                                             4.39                                                                              13.56                                                                             17.16                                                                              (NH)                              41   Cl H amino   C.sub.18 H.sub.13 ClN.sub.4 O                                                            336.8                                                                              64.22                                                                             3.92                                                                              16.68                                                                             10.53                                                                              3320 1690                                                                               1640                                                                               265-7                                                64.19                                                                             3.86                                                                              16.64                                                                             10.54                                                                              3180 1665                                                                               1625                                                                  (NH)                              42   Cl H N-methylpip-                                                                           C.sub.24 H.sub.24 ClN.sub.5 O                                                            434.0                                                                              66.32                                                                             5.50                                                                              15.98                                                                             8.11                                                                               --   1660                                                                               1615                                                                               193-5                          erazino               66.43                                                                             5.54                                                                              16.14                                                                             8.38                                  43   Cl H N-(isopropyl)-                                                                         C.sub.25 H.sub.26 ClN.sub.5 O                                                            448.0                                                                              66.71                                                                             5.94                                                                              15.90                                                                             7.92                                                                               --   1698                                                                               1630                                                                               146-8                          piperazin-1-yl        67.05                                                                             5.89                                                                              15.62                                                                             8.14                                  44   Cl H N-allylpipera-                                                                         C.sub.25 H.sub.24 ClN.sub.5 O                                                            446.0                                                                              67.02                                                                             5.41                                                                              15.62                                                                             8.00                                                                               --   1695                                                                               1635                                                                               187-8                          zin-1-yl              67.33                                                                             5.39                                                                              15.71                                                                             7.97                                  45   Cl H N-(cyclopropyl-                                                                        C.sub.26 H.sub.26 ClN.sub.5 O                                                            460.0                                                                              67.87                                                                             5.73                                                                              15.18                                                                             7.80                                                                               --   1695                                                                               1630                                                                               202-4                          methyl)-piper-        67.90                                                                             5.66                                                                              15.24                                                                             7.73                                            azin-1-yl                                                            46   Cl H N-(dimethyl-                                                                           C.sub.25 H.sub.27 ClN.sub.5 PO.sub.2                                                     496.1                                                                              -- -- -- --  --   1692                                                                               1630                                                                               261-2                          phosphinyl-           60.54                                                                             5.45                                                                              7.16                                                                              14.13                                           methyl)-piper-                                                                 azin-1-yl                                                            __________________________________________________________________________

EXAMPLE 47 8-chloro-1,2-dihydro-2-(N-dimethylphosphinyl-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-on

A mixture of 850 mg of 8-chloro-1,2-dihydro-2-(piperazin-1-yl) methylene-6-(o-chlorphenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one, 1.0 g of chloromethyl-dimethylphosphine oxide, 1.0 g of sodium iodide and 2.0 g of sodium carbonate in 50 ml of dry toluene was stirred under reflux for 24 hours. The cooled solution as partitioned between chloroform and water and the chloroform extract was separated, dried over magnesium sulfate and evaporated to dryness to obtain a gummy solid. The product was chromatographed over silica and was eluted with chloroform to give a solid which on crystallization from methanol-ethyl acetate-ether gave 8-chloro-1,2-dihydro-2-(N-dimethylphosphinylmethyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one with a melting point of 231°-234° C.

I.R. Spectra (KBr disc):

C═O at 1700 cm⁻¹ ; C═N at 1630 cm⁻¹.

EXAMPLE 48 1,2-dihydro-2-(N-dimethylphosphinylmethylpiperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one

Using the method of Example 47, 1,2-dihydro-2-(piperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one was reacted to form 1,2-dihydro-2-(N-dimethylphosphinylmethylpiperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one melting at 245°-247° C.

I.R. Spectra (KBr disc):

C═O at 1695 cm⁻¹ ; C═N at 1630 cm⁻¹.

EXAMPLE 49 8-nitro-1,2-dihydro-2-(N-dimethylphosphinylmethylpiperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one

Using the method of Example 47, 8-nitro-1,2-dihydro-2-(piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo [1,2-a][1,4]-benzodiazepin-1-one was reacted to form 8-nitro-1,2-dihydro-2-(N-dimethylphosphinylmethyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one melting at 245°-248° C.

I.R. Spectra (KBr disc):

C═O at 1700 cm⁻¹ ; C═N at 1642 cm⁻¹

EXAMPLE 50 8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one methanesulfonate

1.1 g of methansulfonic acid were added dropwise to a mixture of 4.6 g of 8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one in 100 ml of anhydrous methylene chloride and 5 ml of methanol. Dry ether was slowly added until crystals formed on scratching and the solution was allowed to crystallize with further ether being added to complete the crystallization. The pale yellow solid was filtered off, washed with ether and crystallized from methylene chloride-methanol to obtain 5.4 g of 8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one methanesulfonate melting at 205°-210° C.

EXAMPLE 51

Tablets were prepared having the following constituents per tablet:

5 mg of 8-chloro-1,2-dihydro-2-(N-methylpiperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo[1,2-a][1,4]-benzodiazepin-1-one and sufficient excipient of lactose, starch, talc and magnesium stearate to obtain a tablet of 100 mg.

The ingredients for gelatin capsules were prepared having the following constituents per capsule:

5 mg of 8-chloro-1,2-dihydro-2-(N-methylpiperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]benzodiazepin-1-one tartrate and sufficient excipient of talc, starch and magnesium stearate for a gelatin capsule weighing 100 mg.

Injectable ampoules were prepared containing a solution having the following constituents: 10 mg of 8-chloro-1,2-dihydro-2-(N-methylpiperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one tartrate and sufficient aqueous solvent to obtain a final volume of 2 ml.

Tablets were prepared having the following constituents per tablets:

5 mg of 8-chloro-1,2-dihydro-2-(N-methylpiperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one and enough excipient of lactose, starch, talc and magnesium stearate to obtain a tablet weighing 100 mg:

Tablets were prepared having the following constituents per tablets:

5 mg of 8-chloro-1,2-dihydro-2-(N-methylpiperazin-1-yl) methylene-6-(o-fluorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one sufficient excipient for a tablet weighing 100 mg of lactose, starch, talc and magnesium stearate.

Tablets were prepared having the following constituents per tablets:

5 mg of 8-nitro-1,2-dihydro-2-(N-methylpiperazin-1-yl) methylene-6-(o- chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one and sufficient excipient for a tablet weighing 100 mg of lactose, starch, talc and magnesium stearate.

Tablets were prepared having the following constituents per tablets:

5 mg of 8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one methanesulfonate and sufficient excipient for a tablet weighing 100 mg of lactose, starch, talc and magnesium stearate.

Tablets were prepared having the following constituents per tablets:

5 mg of 8-chloro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo[1,2-a][1,4]-benzodiazepin-1-one tartrate and sufficient excipient for a tablet weighing 100 mg of lactose, starch, talc and magnesium stearate.

PHARMACOLOGICAL ACTIVITY 1. Antiaggressive activity in mice (AAM)

Groups of 20 randomly selected male mice weighing 25-30 g (Tuck T.O. strain) were given oral doses of either the vehicle alone (10 ml per kg distilled water) or the vehicle plus the test compound. 30 minutes after dosing, pairs of mice were placed under an inverted 1 liter pyrex beaker on a metal grid. The grid was connected to a Palmer square wave stimulator, and the feet of the mice were electrically stimulated with 90 volt pulses of 5 milli-second duration at a frequency of 2 pulses per second for a period of 2 minutes. This procedure provoked fighting in the control mice with a fight being defined as a frontal aggressive attack, usually biting, by either mouse on the other one. The total number of fights in the control group was calculated.

The ED₅₀ of a test compound was that dose which caused a 50% reduction in the number of fights of the batch of mice given that compound as compared with the control batch. [Tedeschi. R. E. et al (1959) J. Pharm. Exptl. Ther. 125.28-34].

The results are shown in the Table below.

2. Anticonvulsant test against maximal electroshock in mice (AEM)

Groups of ten mice were injected orally with the test compound in a vehicle at various dose levels with a control group receiving the vehicle alone. 30 minutes after dosing, each group was then shocked via auricalar electrodes using electroshock apparatus (Ugo Basile ECT apparatus for small mammals). The shocks had a pulse width of 0.2 milliseconds, and a frequency of 100 Hz, and each shock was given for 0.2 seconds at a current of 55 milliamps. The number of mice which underwent tonic extension of their hind limbs was noted. The dose protecting 50% of the mice (TED₅₀), as compared with the control group, was noted, and the results are shown in the Table below.

3. Anticonvulsant test against pentylenetetrazole in mice (AIM)

Groups of ten mice were injected orally with the test compound in a vehicle at various dose levels with a control group receiving the vehicle alone. 30 minutes after dosing, each mouse received a sub-cutaneous injection of 130 mg/kg of pentylenetetrazole challenge (pentylenetetrazole is a central nervous system stimulant), and the mice were then individually housed in observation boxes. A number of mice showing tonic convulsions within 30 minutes of the pentylenetetrazole challenge was noted, and the results for the tonic phase were expressed as a percentage reduction of the control levels. From a constructed dose response curve, the doses protecting 50% of the mice (TED₅₀) against tonus were estimated, and are shown in Table 3 below.

4. Anticonvulsant test against strychnine in mice (ASM)

Groups of ten mice received the test compound and vehicle orally at various dose levels with a control group receiving the vehicle alone. 30 minutes after dosing, each mouse received a sub-cutaneous injection of 1 mg/kg of styrchnine challenge (strychnine is a central nervous system stimulant), and the mice were then housed individually in observation boxes. The number of mice exhibiting tonic convulsions within 15 minutes of the strychnine challenge was noted, and the results for the tonic phase expressed as a percentage reduction of the control value. From a constructed dose response line, the doses protecting 50% of the mice (TED₅₀) against tonus were estimated, and are shown in Table 3 below.

5. Potentiation of hexobarbital in mice (PHM)

A group of ten control mice received an ED₂₀ dose of hexobarbital intraperitoneally (150 mg/kg) of hexobarbital which is a sedative and hypnotic, followed by an oral dose of either a vehicle alone or various oral doses of the vehicle and a test compound. The number of mice which exhibited loss of the righting reflex for 30 seconds half-an-hour after dosing was noted, and a dose response curve was constructed. The dose of test compound which caused 50% of the mice in a group to lose the righting reflex was estimated (ED₅₀), and the results are shown in Table 3 below.

6. Potentiation of chlorprothixene in mice (PXM)

Groups of 10 randomly selected male CFLP mice (Carworth Europe) weighing 20-25 g each were given chlorprothixene intraperitoneally (12.5 mg/kg of chlorprothixene which is a tranquillizer and antipsychotic). This dose consistently caused 10% of mice to lose their righting reflex 30 minutes after dosing. At the same time, the test groups of mice were given orally either vehicle alone (distilled water, 10 ml/kg), or a dose of vehicle plus test compound. Each mouse was then placed individually in a small observation chamber and tested for loss of righting reflex 30 minutes after dosing. The ED₅₀ value of a test compound was the dose which caused loss of the righting reflex in 50% of the number of mice in a group which, in the absence of oral treatment, would not be expected to lose their righting reflex. The results are shown in Table 3 below.

7. Rotating drum test in mice (RDM)

Groups of ten mice were injected orally with vehicle plus the test compound at various dose levels, with a control group receiving the vehicle alone. 30 minutes after dosing, each group of mice was placed on a 30 cm diameter rotating drum revolving at 1 revolution/minute. The mice were placed on the drum against its direction of movement, and the number of mice falling off within a 2 minute period was noted. From the results obtained, a dose response line was constructed, and the dose causing 50% of the mice to fall off the drum (ED₅₀) was estimated. The results are shown in Table 3 below.

8. Mouse Acute Toxicity Test (ATM)

Acute toxicity tests by oral and intraperitoneal routes were conducted using groups of ten mice at various dose levels. The groups were assessed for mortality at 24 hours, and the results are shown in Table 3 below given in mg/kg.

    __________________________________________________________________________             AAM  AMM  ALM         PHM  PXM       ATM                               The compound                                                                           (anti-                                                                              (electro-                                                                           (pentylene-                                                                          ASH   (hexo-                                                                              (chlorpro-                                                                           RDM ip  po                            of Example                                                                             aggression                                                                          shock)                                                                              tetrazole)                                                                           (strychnine)                                                                         barbital)                                                                           thixene)                                                                             (drum)                                                                             (toxicity)                        __________________________________________________________________________     8A      2.65 4.1  0.8   7.1   4.9  5.4   7.1 >1000                                                                              >1000                         8B      4    4.2  0.8   7.4   2.55 6.8   1.7 --  --                            10      4    12.5 1.85  ˜50                                                                            14   29    --  >1000                                                                              >1000                         12      0.2  2.1  0.165 1.8   0.038                                                                               1.6   0.78                                                                               >1000                                                                              >1000                         12B     --   --   --    --    --   2.67  --  --  --                            13      2.2  4.2  0.92  6.6   3.6  4.5   8.6 >1000                                                                              >1000                         15      3.35 12.5 1.15  17    0.66 1.8   24  >1000                                                                              >1000                         21      1.4  8.5  2.35  15    8.3  6.2   --  --  --                            22      0.34 0.27 0.115 1.3   0.21 1.35  2.6 >1000                                                                              >1000                         27      0.92 4.0  >1, <2                                                                               50    3.9  2.6   2.85                                                                               --  --                            28      0.42 0.76 0.028 0.41  1.0  1.1   2.2 --  --                            29      0.26 1.2  0.13  0.46  0.8  1.6   1.5 --  --                            30      0.94 2.2  0.48  5.5   1.1  5.0   1.6 --  --                            30B     0.62 8.3  1.45  30    >50  9.5   7.4 --  --                            31      1.3  2.7  >1, <2                                                                               6.4   3.6  3.2   1.1 --  --                            33      0.5  2.2  0.087 2.3   2.5  1.2   0.56                                                                               --  --                            34      0.48 1.55 --    1.6   2.8  2.35  0.7 --  --                            35      0.03 --   0.15  --    --   0.99  --  --  --                            36      0.64 --   --    --    0.8  --    --  --  --                            37      1.45 --   --    --    0.72 --    --  --  --                            38      0.66 3.5  0.185 1.85  0.064                                                                               1.7   0.29                                                                               --  --                            39      1.0  18.0 0.39  25    0.27 9.6   11.5                                                                               --  --                            40      2.4  >30  1.0   >25   0.06 5.6   8.0 --  --                            46      0.84 --   --    --    --   --    --  --  --                            50      0.42 0.76 0.03  0.41  1.0  1.1   0.85                                                                               --  --                            __________________________________________________________________________

The results obtained show that the compounds of the invention possess a very important activity on the central nervous system as anticonvulsant, anti-anxiety and hypnotic sedatives, and that they have a very low toxicity.

Various modifications of the products and method of the invention may be made without departing from the spirit or scope thereof and it should be understood that the invention is to be limited only as defined in the appended claims. 

We claim:
 1. A compound selected from the group consisting of 1,2-dihydro-6-phenyl-1H,4H-imidazol-[1,2-a][1,4]-benzodiazepin-1-ones of the formula ##STR12## wherein R is selected from the group consisting of hydrogen, halogen, nitro and trifluoromethyl, R₁ is selected from the group consisting of hydrogen and halogen, R₂ is selected from the group consisting of hydrogen and methyl and R₃ and R₄ taken together with the nitrogen atom to which they are attached form a heterocycle selected from the group consisting of morpholino and thiomorpholino optionally substituted with at least one member of the group consisting of alkyl of 1 to 5 carbon atoms, hydroxyalkyl of 1 to 5 carbon atoms, dialkylphosphinylalkyl with 1 to 5 carbon atoms in the alkyl groups, cycloalkylalkyl with 3 to 6 carbon atoms in the ring and 1 to 5 alkyl carbon atoms, alkenyl of 2 to 5 carbon atoms, phenyl and 1-phenyl-5-imidazolyl-4-one, and their non-toxic, pharmaceutically acceptable acid addition salts.
 2. A compound of claim 1 in the form of an acid addition salt with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxialic acid, glyoxylic acid, aspartic acid, and alkanesulfonic acid and an arylsulfonic acid.
 3. A compound of claim 1 selected from the group consisting of 8-chloro-1,2-dihydro-2-(morpholino)-methylene-6-phenyl-1H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one and its non-toxic, pharmaceutically acceptable acid addition salts.
 4. A compound of claim 1 selected from the group consisting of 8-chloro-1,2-dihydro-2-(thiomorpholino)-methylene-6-phenyl-H,4H-imidazo-[1,2-a][1,4]-benzodiazepin-1-one and its non-toxic, pharmaceutically acceptable acid addition salts.
 5. A compositions for the treatment of agitated states, insomnia and psychomatic syndromes comprising an effective amount of at least one compound of claim 1 and a pharmaceutical carrier.
 6. A method for the treatment of states of agitation, insomnia and certain phychosomatic syndromes in warm-blooded animals comprising administering to warm-blooded animals an effective amount of at least one compound of claim
 1. 